Scientists have explained weight loss in cancer
The authors of a new study have discovered a key link between tumor and metabolic reprogramming in cancer cachexia, the extreme debilitation of the body due to cancer.
Chinese medical researchers from Peking University, Dazhou Central Hospital and Nanjing Institute of Translational Medicine, along with a colleague from the Sanford Burnham Prebys Institute for Medical Discovery in La Jolla, USA, conducted experiments on mouse models and discovered what leads to the development of cachexia in patients with cancer. The results of the study are published in the journal Nature Metabolism.
Cachexia - a pathological condition manifested by an extreme degree of weight loss at the expense of muscle and adipose tissue, weakness and impaired vital processes - occurs in 50-80% of cancer patients and in 20% of cases leads to their death. It is associated with chronic obstructive pulmonary disease (COPD), heart failure, kidney disease, infectious and inflammatory diseases. Excess cytokines, myostatin protein and glucocorticoids, as well as deficiency of testosterone and insulin-like growth factor 1 have been cited among the main causes of cachexia. But the mechanism responsible for triggering this metabolic syndrome has remained unclear.
The authors of the new study tested the levels of metabolites - products of metabolism - in the blood of male laboratory mice aged 8-10 weeks with cachexia caused by the presence of Lewis lung carcinoma. The animals were pre-distributed into two groups, one of which was the control group and received placebo instead of cancer cells. After the experiment, the rodents were killed.
The study of samples from the subjects helped to identify lactate - a product of cellular metabolism, a derivative of lactic acid - as the main metabolite, the level of which correlated closely with a decrease in body weight. More precisely, it was about its receptor GPR81.
When scientists implanted animals with human cancer cells, it turned out that the increased level of lactate due to GPR81 provokes extensive transformation of white adipose tissue (consists mainly of white adipocytes), including its darkening and lipolysis - the process of breaking down fats into fatty acids. As a result, weight loss occurred.
"Our results showed that the GPR81 receptor is a key link between tumor and metabolic reprogramming in cancer cachexia. We also demonstrated that catabolic remodeling of white adipose tissue is an early pathological state in cancer cachexia, although skeletal muscle atrophy acts as a major contributor to impaired physical functioning in patients with cachexia. Based on our observations, fat loss may occur in some cancer patients without a decrease in muscle mass. The essential role of adipose tissue loss in the development of cancer cachexia is also evidenced by the fact that depletion of key lipolysis enzymes facilitates cachexic phenotypes in mice," the scientists added.
A chronic increase in blood lactate levels was enough to cause white adipose tissue "browning" (turning brown), lipolysis, muscle atrophy and finally weight loss - this was confirmed when metabolites were analyzed in men and women with cachexia. The level of this product of cellular metabolism decreased markedly after the removal of lung tumors: on this basis, the scientists assumed that the tumor is the main cause of elevated blood lactate levels, although lactate infusion was sufficient to trigger cachexia in rodents without tumors.
Consequently, learning how to target the GPR81 receptor could provide a way to treat such a life-threatening complication in cancer patients. However, this will require further research.